Transdermal adhesive compositions, devices and methods

ABSTRACT

A stable transdermal adhesive composition comprising: an adhesive comprising a washed polymerization reaction product of at least two ethylenically unsaturated monomers; and at least one pharmaceutically active compound which is susceptible to oxidative degradation; wherein the at least two ethylenically unsaturated monomers, if present in the adhesive as unreacted monomers, are present at a level of less than 200 ppm of total unreacted monomer, based upon the total weight of the adhesive, methods of making the composition, a transdermal drug delivery device using the composition, methods of making the device, and methods of delivery the pharmaceutically active compound are provided.

BACKGROUND

Transdermal administration of a drug can provide a number of possibleadvantages, such as avoidance of first-pass metabolism, avoidance ofgastro-intestinal irritation, sustained release, and improved patientcompliance with treatment regimens. Transdermal drug delivery devicesused for this purpose are typically designed to deliver atherapeutically effective amount of drug across the skin of a subject.The drug is normally incorporated into a carrier, such as a liquid, gel,solid matrix, or pressure sensitive adhesive. Reservoir type devices mayinclude a membrane that controls the rate of drug release to the skin,while other devices may have a drug dispersed or dissolved in a matrixsuch as a pressure sensitive adhesive.

Drug dosages have been directly incorporated into the adhesive portionof transdermal patches where the adhesive is used to secure the patch toskin. Efforts to remove residual monomer components and the like fromadhesives for contacting skin have been reported with the aim ofreducing skin irritation, improving adhesive properties, such asadhesion, and/or reducing unpleasant odors.

However, there continues to be an interest in and a need for improvedtransdermal drug delivery devices and adhesive compositions usedtherein.

SUMMARY OF THE INVENTION

It has now been found that pharmaceutically active compounds which aresubject to oxidative degradation can be incorporated into certainadhesive compositions, providing compositions with enhanced stability.Moreover, it has now been found that pharmaceutically active compoundswhich are subject to oxidative degradation, and therefore require anantioxidant to provide sufficient stability in a carrier, can beincorporated into certain adhesive compositions without the need for anantioxidant.

Accordingly, in one embodiment there is provided a transdermal adhesivecomposition comprising:

an adhesive comprising a washed polymerization reaction product of atleast two ethylenically unsaturated monomers; and

at least one pharmaceutically active compound which is susceptible tooxidative degradation;

wherein the at least two ethylenically unsaturated monomers, if presentin the adhesive as unreacted monomers, are present at a level of lessthan 200 ppm of total unreacted monomer, based upon the total weight ofthe adhesive; and

wherein any free radical initiator, if present in the adhesive, ispresent at a level of less than 20 ppm, based upon the total weight ofthe adhesive.

In another embodiment, there is provided a transdermal adhesivecomposition comprising:

an adhesive comprising a washed polymerization reaction product of atleast two ethylenically unsaturated monomers; and

(S)—N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate or apharmaceutically acceptable salt thereof;

wherein the at least two ethylenically unsaturated monomers, if presentin the adhesive as unreacted monomers, are present at a level of lessthan 200 ppm of total unreacted monomer, based upon the total weight ofthe adhesive.

In another embodiment, there is provided a transdermal drug deliverydevice comprising:

a transdermal adhesive composition comprising:

-   -   an adhesive comprising a washed polymerization reaction product        of at least two ethylenically unsaturated monomers; and    -   at least one pharmaceutically active compound which is        susceptible to oxidative degradation;    -   wherein the at least two ethylenically unsaturated monomers, if        present in the adhesive as unreacted monomers, are present at a        level of less than 200 ppm of total unreacted monomer, based        upon the total weight of the adhesive; and

a backing sheet coated with the transdermal adhesive composition,wherein the transdermal adhesive composition coating covers at least aportion of a major surface of the backing sheet.

In another embodiment, there is provided a method of making a stabletransdermal adhesive composition comprising:

providing a polymerization reaction product of at least twoethylenically unsaturated monomers; and wherein the polymerizationreaction product is dissolved and/or dispersed in a first liquid;

separating at least a portion of the polymerization reaction productfrom the first liquid to provide a first washed polymerization reactionproduct;

dissolving or dispersing the first washed polymerization reactionproduct in a second liquid;

separating at least a portion of the first washed polymerizationreaction product from the second liquid to provide a second washedpolymerization reaction product;

wherein the at least two ethylenically unsaturated monomers, if presentin the second washed polymerization reaction product, are present at alevel of less than 200 ppm of total unreacted monomer, based upon thetotal weight of the second washed polymerization reaction product; and

combining the second washed polymerization reaction product with atleast one pharmaceutically active compound which is susceptible tooxidative degradation to form a stable transdermal adhesive composition.

In another embodiment, there is provided a method of making a stabletransdermal drug delivery device comprising:

providing a transdermal adhesive composition according to any one of theabove composition embodiments or any embodiment thereof described hereinor a transdermal adhesive composition made according to the above methodembodiment or any embodiment thereof described herein; and

coating a backing sheet with the transdermal adhesive composition,wherein the transdermal adhesive composition coating covers at least aportion of a major surface of the backing sheet.

In a further embodiment, there is provided a method of delivering apharmaceutically active compound to a mammal comprising the steps of:

providing a transdermal adhesive composition according to any one of theabove composition embodiments or any embodiment thereof described hereinor a transdermal adhesive composition made according to the above methodembodiment or any embodiment thereof described herein or a deviceaccording to the above device embodiment or any embodiment thereofdescribed herein or a device made according to the above method ofmaking a device embodiment or any embodiment thereof described herein;

positioning the transdermal adhesive composition on the skin of themammal; and

allowing the composition to remain on the skin for a time sufficient topermit systemic delivery of the pharmaceutically active compound;

wherein the pharmaceutically active compound is susceptible to oxidativedegradation.

DEFINITIONS

The following terms are used herein according to the followingdefinitions.

As used herein, “washing” or “washed” refers to a polymerizationreaction product which has been dissolved or dispersed in a liquid, suchas an organic solvent, and then separated from the liquid, such that thelevel of unreacted monomer is reduced, for example, to less than 200 ppmof total unreacted monomer, based upon the total weight of the washedpolymerization reaction product or the adhesive comprising the washedpolymerization reaction product. For certain embodiments, preferably thelevel of unreacted monomer is reduced to less than 100 ppm, even morepreferably less than 50 ppm of total unreacted monomer.

“Stable” means both chemically and physically stable. As used herein“physically stable” compositions are those that do not significantlychange due to substantial precipitation, crystallization, phaseseparation, and the like, from their original condition during storageat 25° C. for at least 3 months, and preferably for at least 6 months.As used herein, “chemically stable” compositions retain an average of atleast 98% of the pharmaceutically active compound after aging for 2months at 60° C. in ambient humidity or degrade the pharmaceuticallyactive compound, forming less than 2 percent by weight degradationproducts based upon the total starting weight of the pharmaceuticallyactive compound. For certain embodiments, preferably stable compositionsretain an average of at least 99% of the pharmaceutically activecompound after aging for 2 months at 60° C. in ambient humidity ordegrade the pharmaceutically active compound, forming less than 1percent by weight degradation products based upon the total startingweight of the pharmaceutically active compound. The level ofpharmaceutically active compound or degradation product thereof ispreferably determined using gas chromatography or high performanceliquid chromatography using appropriate standards and controls.

As used herein, “susceptible to oxidative degradation” refers topharmaceutically active compounds which may be combined with anantioxidant when made into a drug product to keep the active compoundstable during the life of the drug product.

As used herein, “essentially free of any added antioxidant” refers to atransdermal adhesive composition to which no antioxidant has been addedfor the purpose of preventing a pharmaceutically active compoundsusceptible to oxidative degradation from forming total drug impuritiesin excess of 2% within two years at room temperature or 2 months at 60°C. with ambient humidity. For certain embodiments, preferably less than0.1%, more preferably less than 0.05%, most preferably less than 0.01%antioxidant is present in the transdermal adhesive composition which is“essentially free of any added antioxidant.”

“Subject” and “patient” includes humans, sheep, horses, cattle, pigs,dogs, cats, rats, mice, or other mammals.

The terms “comprises” and variations thereof do not have a limitingmeaning where these terms appear in the description and claims.

As used herein, “a,” “an,” “the,” “at least one,” and “one or more” areused interchangeably. The term “and/or” means one or all of the listedelements.

Also herein, the recitations of numerical ranges by endpoints includeall numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2,2.75, 3, 3.80, 4, 5, etc.).

The above summary of the present invention is not intended to describeeach disclosed embodiment or every implementation of the presentinvention. The description that follows more particularly exemplifiesillustrative embodiments. In several places throughout the application,guidance is provided through lists of examples, which examples can beused in various combinations. In each instance, the recited list servesonly as a representative group and should not be interpreted as anexclusive list.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present invention provides stable transdermal adhesive compositionswith enhanced stability, in certain embodiments, preferably without aneed for adding an antioxidant or with a reduced level of antioxidantwhen incorporating pharmaceutically active compounds susceptible tooxidative degradation.

FDA Guidance Q3B(R2): Impurities in New Drug Products indicates that fora drug product to be considered stable, total drug impurities must notexceed 2%. In order to sufficiently limit the formation of drugimpurities associated with oxidative degradation, antioxidants have beenadded to drug compositions, thereby achieving the required level ofstability. For example, U.S. Pat. No. 6,335,031 reports compositions,containing a cholinesterase inhibitor((S)—N-ethyl-3-[(1-dimethylamino)ethyl]-N-methylphenyl carbamate) with0.1% tocopherol (antioxidant), with 1.3% degradation products after 2months at 60° C., but with 4.46% degradation products without theantioxidant.

Applicants have now found stable transdermal adhesive compositionscomprising an adhesive comprising a washed polymerization reactionproduct of at least two ethylenically unsaturated monomers, and at leastone pharmaceutically active compound which is susceptible to oxidativedegradation. The polymerization reaction product is washed such that theat least two ethylenically unsaturated monomers, if present in theadhesive as unreacted monomers after washing, are reduce to at a levelof less than 200 ppm of total unreacted monomer, based upon the totalweight of the adhesive. For certain embodiments, preferably suchcompositions are stable without the need to add any antioxidant. Forcertain embodiments, such compositions are stable even when an amount ofantioxidant is used which is less than, for example, half the amount ofantioxidant needed when an unwashed polymerization reaction product isused. For certain of these embodiments, the amount of antioxidant isless than 25 percent or less than 10 percent of the amount ofantioxidant needed when an unwashed polymerization reaction product isused.

The adhesive is preferably a pressure sensitive adhesive, and, exceptfor the washing described herein, the polymerization reaction productwhich the adhesive comprises can be made by free radical polymerizationof the ethylenically unsaturated monomers using known radicalpolymerization methods. See for example, U.S. Pat. No. RE 24,906(Ulrich). Thermally or photochemically activated free radical-forminginitiators may be used to carry out the polymerization reaction.Preferably, such initiators are other than peroxide initiators. Suitablethermally activated initiators include azo compounds such as2,2′-azobis(isobutyronitrile), 2,2′-azobis(2,4-dimethylvaleronitrile),and the like. Suitable photochemically activated initiators include, forexample, benzoin ethyl ether, 2,2-dimethoxy-2-phenylacetophenone, andthe like. The polymerization reaction can be conveniently carried out ina solvent using conventional free radical solution polymerizationmethods.

Such polymerization reactions result in the formation of a polymer alongwith some level of unreacted monomers and initiator. The present washedpolymerization reaction product has significantly reduced levels of bothunreacted monomers and initiator. While the reduced levels of unreactedmonomers and initiator indicate that the polymerization reaction productis sufficiently washed to provide the stable transdermal adhesivecomposition, the reason for the surprising degree of stability soobtained is not known. Moreover, this result is achieved without usingpurification steps involving the addition of an oxidizing agent and areducing agent which react with one another to generate free radicalswhich can initiate further polymerization of the unreacted monomerincluded with the polymerization reaction product.

For certain embodiments, including any one of the above embodiments,preferably the at least two ethylenically unsaturated monomers, ifpresent in the adhesive, are present at a level of less than 100 ppm oftotal unreacted monomer, based upon the total weight of the adhesive,more preferably less than 50 ppm or below the detectable level. Inaddition, when an acrylamide or methacrylamide is used to prepare thepolymerization reaction product, these unreacted monomers, if present inthe adhesive, are present at a level of less than 30 ppm based upon thetotal weight of the adhesive, preferably less than 16 ppm or even lessthan 5 ppm.

For certain embodiments, including any one of the above embodiments,preferably any free radical initiator, if present in the adhesive, ispresent at a level of less than 20 ppm, based upon the total weight ofthe adhesive comprising the washed polymerization reaction product. Forcertain of these embodiments, preferably any free radical initiator, ifpresent in the adhesive, is present at a level of less than 10 ppm, morepreferably less than 5 ppm.

For certain embodiments, including any one of the above embodiments, theat least two ethylenically unsaturated monomers comprise anethylenically unsaturated group selected from the group consisting ofacryloyl, methacryloyl, vinyl, and a combination thereof.

For certain embodiments, including any one of the above embodiments, theadhesive comprises the copolymerization product of at least one firstmonomer selected from the group consisting C₄ to C₁₂ alkyl acrylatemonomers, C₄ to C₁₂ alkyl methacrylate monomers, and combinationsthereof; and at least one second monomer selected from the groupconsisting of acrylamide, N,N-diethylacrylamide, methacrylamide, vinylacetate, vinyl alcohol, N-vinyl-2-pyrrolidone, 2-hydroxyethyl acrylate,2-hydroxyethyl methacrylate, hydroxpropyl acrylate, glyceryl acrylate,2-ethoxyethyl acrylate, 2-ethoxyethoxyethyl acrylate, tetrahydrofurfurylacrylate, acrylic acid, methacrylic acid, pyrrolidonylethyl acrylate,2-carboxyethyl acrylate, and combinations thereof. For certain of theseembodiments, preferably the at least one first monomer is selected fromthe group consisting of isooctyl acrylate, 2-ethylhexyl acrylate,cyclohexyl acrylate, 2-methylbutyl acrylate, butyl acrylate, andcombinations thereof. For certain of these embodiments, preferably theat least one second monomer is selected from the group consisting ofacrylamide, vinyl acetate, and a combination thereof. The amount of theat least one first monomer, is typically between about 40% and about98%, more typically between about 60% and about 95%, and most preferablybetween about 70% and about 90% by weight of the resulting copolymercomposition. The amount of the at least one second monomer is typicallybetween about 2% and about 60%, more typically between about 3% andabout 40%, and most preferably between about 4% and about 30% by weightof the copolymer composition. The copolymers comprising the pressuresensitive adhesive may optionally further comprise other radicallypolymerizable monomers that are well known in the art. The copolymerscomprising the pressure sensitive adhesive may optionally furthercomprise a substantially linear macromonomer copolymerizable with theother monomers. Suitable macromonomers include polymethylmethacrylate,styrene/acrylonitrile copolymer, polyether, and polystyrenemacromonomers.

For certain embodiments, including any one of the above embodiments, theadhesive comprises the co-polymerization product of isooctyl acrylate,acrylamide, and vinyl acetate. For certain of these embodiments, theisooctylacrylate is 70-80%, the acrylamide is 3-7%, and the vinylacetate is 15-25% of the copolymerization product on a weight basis. Forcertain of these embodiments, the isooctyl acrylate/acrylamide/vinylacetate weight ratio is 75/5/20.

Additional examples of adhesives which may be used in the presentcompositions, methods, and devices include copolymers of isooctylacrylate/acrylamide (for example, about 93/7 weight ratio); copolymersof ethylhexyl acrylate, butyl acrylate, and vinyl acetate; DUROTAK87-2353, 387-2353, 387-2051, and 387-2052 (National Starch and ChemicalCompany, Zutphen, Holland); PLASTOID B (Rohm, Darmstadt, Germany); andEUDRAGIT E 100 (Rohm, Darmstadt, Germany).

For certain embodiments, including any one of the above embodiments,pharmaceutically active compounds which are susceptible to oxidativedegradation are those which when not used in the present compositionsmay be combined with an antioxidant in order to prevent total drugimpurities from exceed 2% within two years at room temperature or 2months at 60° C. with ambient humidity. For certain of theseembodiments, the pharmaceutically active compound includes at least onegroup selected from the group consisting of tertiary amino, secondaryamino, benzylic hydrogen-containing group, and combinations thereof. Abenzylic hydrogen-containing group includes a hydrogen atom bonded to acarbon atom, the carbon atom being bonded directly to a phenyl group.For certain embodiments, the pharmaceutically active compound includesat least one tertiary amino group. Pharmaceutically active compoundswhich contain at least one of these groups are subject to oxidativedegradation and may be used in the compositions, devices, and methodsdescribed herein without the addition of an antioxidant or with theaddition of less than 50%, less than 25%, or less than 10% the amount ofantioxidant needed to achieve an equivalent degree of stability whenused in an unwashed adhesive. For certain of these embodiments, thepharmaceutically active compound is selected from the group consistingof: rivastigmine ((S)—N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenylcarbamate), buprenorphine, etidocaine, ropivacaine, clonidine,lidocaine, letrozole, fentanyl, indapamide, apomorphine,propylnorapomorphine, salbutamol, lisuride, dihydroergotamine,pergolide, terguride, proterguride, propranolol, imipramine,guanethidine, cyproheptadine and a pharmaceutically acceptable salt ofany one of the preceding compounds. For certain of these embodiments,preferably the pharmaceutically active compound is selected from thegroup consisting of: rivastigmine, lidocaine, buprenorphine, etidocaine,ropivacaine, fentanyl, clonidine, and a pharmaceutically acceptable saltof any one of the preceding compounds. For certain of these embodiments,most preferably the pharmaceutically active compound is rivastigmine((S)—N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate) or apharmaceutically acceptable salt thereof.

As indicated above, the present transdermal adhesive compositions havebeen found to be stable without the need for adding any antioxidant.Accordingly, for certain embodiments, including any one of the aboveembodiments, the composition is essentially free of any addedantioxidant. Examples of such antioxidants include butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), tertiary butylhydroquinone (TBHQ), propyl gallate, ascorbic acid and esters thereof,e.g., ascorbyl palmitate, tocopherol and esters thereof, e.g.,tocopherol acetate, and including isomers thereof, polyphenolicantioxidants, flavinoids, isoflavinoids, neoflavinoids, quercetin,rutin, epicatechins, resveratrol, thioglycerol, thioglycolic acid,thiourea, acetylcysteine, sodium bisulfite, sodium sulfite, sodiummetabisulfite, cyclodextrins (to cover site of active pharmaceuticalcompound subjected to oxidation), and carotenoids. For certainembodiments, the antioxidant that is not added is butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate,ascorbic acid and esters thereof, e.g., ascorbyl palmitate, tocopheroland esters thereof, e.g., tocopherol acetate, including isomers thereof,e.g., alpha-tocopherol, or a combination thereof.

As described above, the stable transdermal adhesive composition isprepared by providing a polymerization reaction product of at least twoethylenically unsaturated monomers; and wherein the polymerizationreaction product is dissolved and/or dispersed in a first liquid;separating at least a portion of the polymerization reaction productfrom the first liquid to provide a first washed polymerization reactionproduct; dissolving or dispersing the first washed polymerizationreaction product in a second liquid; separating at least a portion ofthe first washed polymerization reaction product from the second liquidto provide a second washed polymerization reaction product; wherein theat least two ethylenically unsaturated monomers, if present in thesecond washed polymerization reaction product, are present at a level ofless than 200 ppm of total unreacted monomer, based upon the totalweight of the second washed polymerization reaction product; andcombining the second washed polymerization reaction product with atleast one pharmaceutically active compound which is susceptible tooxidative degradation to form a stable transdermal adhesive composition.In some instances, depending upon the pharmaceutically active compoundto be used, one or more additional washing steps may be included forincreased stability of the active. Accordingly, for certain of theseembodiments, the method further comprises dissolving or dispersing thesecond washed polymerization reaction product in a third liquid;separating at least a portion of the second washed polymerizationreaction product from the third liquid to provide a third washedpolymerization reaction product; and combining the third washedpolymerization reaction product instead of the second washedpolymerization reaction product with the at least one pharmaceuticallyactive compound which is susceptible to oxidative degradation to formthe stable transdermal adhesive composition. Here, the at least twoethylenically unsaturated monomers, if present in the third washedpolymerization reaction product, are present at a level of less than 200ppm of total unreacted monomer, based upon the total weight of the thirdwashed polymerization reaction product.

For certain embodiments, preferably the polymerization reaction productis dissolved and then precipitated out by adding a wash liquid which isa poor solvent for polymer included in the polymerization reactionproduct. A more thorough washing of the polymerization reaction productis thereby provided as compared with simply dispersing thepolymerization reaction product in a wash liquid and then conducting theseparation step. Accordingly, for certain embodiments, including any oneof the above method embodiments, the separating, in each instance, iscarried out by adding a wash liquid to the dissolved polymerizationreaction product, allowing polymerization reaction product toprecipitate, and separating the precipitated from the liquid(combination of wash liquid and liquid in which the polymerizationreaction product was dissolve), to provide washed polymerizationreaction product.

Suitable wash liquids include any nonreactive liquid which is a poorsolvent for the polymer and in which unreacted monomer and initiatorhave some solubility. Examples include methanol, isopropyl alcohol,methanol/water mixtures, isopropyl alcohol/water mixtures, and the like.

Suitable liquids (first, second, third, etc.) for dissolving thepolymerization reaction product include organic solvents which dissolvethe polymerization reaction product and which are miscible with the washliquid. Examples include acetone, ethyl acetate, ethyl acetate/methanolmixtures, preferably with not more than 30% methanol, and the like. Whendispersing (including not fully dissolving) the polymerization reactionproduct, the suitable liquids (first, second, third, etc.) may includethe wash liquids described above, or alternatively, the suitable liquidsmay be the wash liquids.

For certain embodiments, including any one of the above methodembodiments, the method further comprises polymerizing the at least twoethylenically unsaturated monomers dissolved in the first liquid toprovide the polymerization reaction product dissolved and/or dispersedin the first liquid.

For certain embodiments, including any one of the above methodembodiments, preferably the at least two ethylenically unsaturatedmonomers, if present in the washed polymerization reaction productcombined with the at least one pharmaceutically active compound, arepresent at a level of less than 100 ppm, based upon the total weight ofthe washed polymerization reaction product. For certain of theseembodiments the level is less than 50 ppm.

For certain embodiments, including any one of the above methodembodiments, preferably any free radical initiator, if present in thewashed polymerization reaction product combined with at least onepharmaceutically active compound, is present at a level of less than 20ppm, based upon the total weight of the washed polymerization reactionproduct. For certain of these embodiments, preferably the level is lessthan 10 ppm, more preferably less than 5 ppm.

For certain embodiments, including any one of the above methodembodiments, preferably an antioxidant is not added to the stabletransdermal adhesive composition.

The transdermal adhesive compositions typically contain atherapeutically effective amount of the pharmaceutically activecompound, for example, rivastigmine. This amount will vary according tothe form of the drug used, such as a particular salt form, theparticular condition to be treated, the amount of time the compositionis allowed to remain in contact with the skin of the subject, and otherfactors known to those of skill in the art. Generally, the amount ofdrug present in the transdermal drug delivery composition will be about0.1 to about 40 percent by weight, typically about 5.0 to about 25percent by weight, and more typically about 10.0 to about 20.0 percentby weight based on the total weight of the composition.

The transdermal adhesive compositions may optionally contain additives,including, for example excipients, skin permeation enhances, andsolubilizers. Suitable excipients include, for example, amine oxides,unsaturated fatty acids, isopropyl myristate, lauroglycol, α-terpineol,polyethylene glycol, sorbitan esters, lactic acid, anddimethylsulfoxide. In one embodiment, the excipient is a skin permeationenhancer. Permeation enhancers are desirable excipients for use intransdermal drug delivery, because the skin typically presents aneffective barrier to passage of most drug molecules. Amine oxides,unsaturated fatty acids, α-terpineol, polyethylene glycol, and sorbitanmonooleate are preferred permeation enhancers. Amine oxides andunsaturated fatty acids are particularly effective permeation enhancers.Amine oxides include, for example, lauramine oxide and2-hexadecyldimethylamine oxide. Unsaturated fatty acids include, forexample, oleic acid, linoleic acid, and linolenic acid. Oleic acid is apreferred unsaturated fatty acid. Sorbitan esters include, for example,sorbitan monooleate, sorbitan laurate, and sorbitan stearate. Sorbitanmonooleate is a preferred sorbitan ester. Isopropyl myristate andlauroglycol are also suitable for use as permeation enhancers. Thepermeation enhancer should be present in an amount sufficient to allowpermeation of a sufficient amount of the pharmaceutically activecompound across the skin so as to have a desired therapeutic effect. Theamount of permeation enhancer is typically less than about 40% by weightof the total composition and more typically less than about 30%. Thepermeation enhancers are dispersed, typically substantially uniformly,and more typically dissolved in the composition.

In another embodiment of the invention, the excipient is a solubilizerof the pharmaceutically active compound, or a pharmaceuticallyacceptable salt thereof.

Solubilizers may be used both to increase the amount of total dissolveddrug in the composition and/or to increase the solubility of drug in oneor more layers of the skin. The solubility of the pharmaceuticallyactive compound in the solubilizer is typically greater than thesolubility of the pharmaceutically active compound in the pressuresensitive adhesive. The amount of solubilizer used will vary dependingon the desired dosing levels and durations, but the amount ofsolubilizer is typically less than about 35% by weight of the totalcomposition and more typically less than about 25%. The total combinedamount of permeation enhancer and solubilizer in the composition istypically less than about 40% by weight of the total composition andmore typically less than about 30%. The solubilizers are dispersed,preferably substantially uniformly, and more preferably dissolved in thecomposition.

The transdermal adhesive compositions may optionally contain otheradditives or excipients, such as plasticizers, crosslinking agents, andcolorants. Optional additives are dispersed, preferably substantiallyuniformly, and more preferably dissolved in the composition.

Transdermal drug delivery devices can be made using the transdermaladhesive compositions described above (including those made by the abovemethods) by coating a backing sheet with the transdermal adhesivecomposition, wherein the transdermal adhesive composition coating coversat least a portion of a major surface of the backing sheet.

Transdermal drug delivery devices that include compositions of theinvention can be made in the form of an article such as a tape, a patch,a sheet, a dressing or any other form known to those skilled in the art.Generally, the device will be in the form of a patch of a size suitableto deliver a selected amount of drug through the skin.

For certain embodiments, including any one of the above deviceembodiments, the device will have a surface area of at least 1 cm² or atleast 5 cm², and not more than 100 cm² or not more than 40 cm².

The devices can include a release liner that covers and protects theskin-contacting surface, e.g., the transdermal adhesive composition,prior to application to a subject. Suitable release liners include, butare not limited to, conventional release liners comprising a known sheetmaterial, such as a polyester web, a polyethylene web, a polypropyleneweb, or a polyethylene-coated paper coated with a suitable fluoropolymeror silicone based coating. The devices can be packaged individually in afoil-lined pouch for storage, and may alternatively be provided in arolled or stacked form suitable for use with a dispensing apparatus.

Examples of flexible backing materials employed as conventional tapebackings that can be use as the backing sheet. Examples include thosemade from polymer films such as polypropylene; polyethylene,particularly low density polyethylene, linear low density polyethylene,metallocene polyethylenes, and high density polyethylene; polyvinylchloride; polyester (e.g., polyethylene terephthalate); ethylene-vinylacetate copolymer; polyurethane; cellulose acetate; and ethyl cellulose.Backings that are layered, such as polyethyleneterephthalate-aluminum-polyethylene composites, are also suitable.Fabrics and non-wovens are likewise suitable. In one implementation, thebacking is a continuous polymeric film that prevents ingress of externalmoisture into the transdermal adhesive composition, for example, fromhigh ambient humidity and/or activities such as showering and bathing.Examples of such continuous films include, but are not limited to,polyurethane, polyethylene, and polyester.

The backing thickness is typically more than 10 μm, more typically morethan 20 μm, and most preferably more than 40 μm. The backing thicknessis typically less than 150 μm, more typically less than 125 μm, and mostpreferably less than 100 μm.

The transdermal adhesive composition can be prepared by combining theadhesive (washed polymerization reaction product optionally combinedwith a tackifier and/or other adhesive component), pharmaceuticallyactive compound, and optional additives such as a permeation enhancerand/or solubilizers, with an organic solvent (e.g., ethyl acetate,isopropanol, methanol, acetone, 2-butanone, ethanol, toluene, alkanes,and mixtures thereof) to provide a coating composition. The mixture isshaken or stirred until a homogeneous coating composition is obtained.The resulting composition is then applied to a release liner usingconventional coating methods (e.g., knife coating or extrusion diecoating) to provide a predetermined uniform thickness of coatingcomposition. Non-continuous or discontinuous coatings may be preparedusing methods such as stripe coating, screen-printing, and ink-jetprinting.

The transdermal adhesive compositions and devices provided herein can beused to treat conditions for which the pharmaceutically active compoundsusceptible to oxidative degradation has been found to be effective.These treatments generally involve a method of delivering thepharmaceutically active compound to a mammal comprising the steps of:providing a transdermal adhesive composition according to any one ofabove composition or method embodiments or providing a device accordingto any one of the above device embodiments or method of making a deviceembodiments; positioning the transdermal adhesive composition on theskin of the mammal; and allowing the composition to remain on the skinfor a time sufficient to permit systemic delivery of thepharmaceutically active compound and/or achieve the desired therapeuticresult. The period of time for such treatment can be between about 6hours and about 14 days, typically between about 1 day and about 7 days,and more typically between about 1 day and about 4 days.

The following examples are provided to more particularly illustratevarious embodiments of the present invention, but the particularmaterials and amounts thereof recited in these examples, as well asother conditions and details are in no way intended to be limit thisinvention.

EXAMPLES Materials Preparation of the Copolymers

The copolymers used in the examples that follow were prepared generallyaccording to the methods described below. The inherent viscosity valueswhich are reported below were measured by conventional means using aCannon-Fenske #50 viscometer in a water bath controlled at 27° C. tomeasure the flow time of 10 millimeters of the polymer solution (0.15 gof polymer per deciliter of ethyl acetate). The test procedure andapparatus are described in detail in Textbook of Polymer Science, F. W.Billmeyer, Wiley Interscience, Second Edition (1971), pages 84 and 85.

Copolymer A. Preparation of Isooctyl Acrylate/Acrylamide/Vinyl Acetate(75/5/20) Copolymer

Isooctyl acrylate (IOA) (75 g), acrylamide (ACM) (5 g), vinyl acetate(VOAc) (20 g), ethyl acetate (136.5 g), and methanol (13.5 g) were addedto a 1 quart vessel and the vessel was purged with nitrogen (2 minutes,1.5 liters per minute nitrogen flow).2,2′-azobis(2,4-dimethylvaleronitrile) (0.05 g) was added and thereaction was agitated at 42° C. for 6 hours. An additional portion of2,2′-azobis(2,4-dimethylvaleronitrile) (0.05 g) was added and the vesselwas again purged with nitrogen (2 minutes, 1.5 liters per minutenitrogen flow). The reaction was maintained at 42° C. for an additional22 hours. The temperature was raised to 57° C. and the reaction wasmaintained an additional 6 hours. The resulting polymerization reactionproduct was diluted with ethyl acetate (30.6 g) and methanol (5 g). Thepercent solids of the resultant copolymer solution was 31 weight %. Themeasured inherent viscosity was 1.34 dL/g.

Copolymer B. Preparation of Solvent WashedIsooctylAcrylate/Acrylamide/Vinyl Acetate (75/5/20) Copolymer GeneralDescription of the Copolymer Solvent Washing Process:

A wash liquid, i.e., a non-solvent or poor solvent for the copolymer(for example, methanol) was added to a solution of copolymer adhesive,resulting in precipitation of the copolymer. The liquid phase wasdecanted, and the precipitated polymer was redissolved by the additionof solvent (for example, ethyl acetate). The washing process wasrepeated up to two more times (for total washing steps up to threetimes). The resulting solution was then concentrated by distillation.The effect of the washing steps was to remove substantial amounts of lowmolecular weight material from the original solution, providing acopolymer substantially free from impurities.

Detailed Description of the Copolymer Washing Process:

100 g of Copolymer A (75/5/20 IOA/ACM/VOAc, 31 weight % solids in 90/10ethyl acetate/methanol, prepared as described above) was added to aclean vessel and methanol (200 g) was added without agitation. Themixture was then vigorously shaken using a mechanical shaker for 10minutes to create a flocculate precipitate. The mixture was maintainedwithout agitation for 2 hours. The precipitate settled to the bottom ofthe vessel as a gummy solid. The liquid was decanted from the vessel. Anadditional 50 g of ethyl acetate was added to the solid and the vesselwas agitated for one hour (sample after first wash treatment). A secondportion of methanol (200 g) was added without agitation. The mixture wasthen vigorously shaken using a mechanical shaker for 10 minutes tocreate a flocculate precipitate. The mixture was maintained withoutagitation for 2 hours. The precipitate settled to the bottom of thevessel as a gummy solid. The liquid was decanted from the vessel. Anadditional 50 g of ethyl acetate was added to the solid and the vesselwas agitated for one hour (sample after second wash treatment). A thirdportion of methanol (200 g) was added without agitation. The mixture wasthen vigorously shaken using a mechanical shaker for 10 minutes tocreate a flocculate precipitate. The mixture was maintained withoutagitation for 2 hours. The precipitate settled to the bottom of thevessel as a gummy solid. The hazy liquid was decanted from the vessel.The resulting washed polymerization reaction product was dissolved in 50mL of ethyl acetate and distilled under vacuum at 120° F. (49° C.) toprovide a copolymer solution at 32 weight % solids in ethylacetate/methanol (Copolymer B, sample after third wash treatment). Themeasured inherent viscosity was 1.45 dL/g.

Example 1

Copolymer A and samples of Copolymer A after one, two, and three (aboveCopolymer B) wash treatments were analyzed for residual monomers and thefree radical initiator by gas chromatography using an HP-6850 gaschromatograph equipped with a split/splitless injection port and flameionization detector (Hewlett Packard, Palo Alto, Calif.). The analyticalcolumn used was a DB-1 J&W 125-1035 capillary column (AgilentTechnologies, Santa Clara, Calif.). The injection port was set to 250°C. and the flame ionization detector was set to 300° C. The oventemperature was set to 100° C. and the temperature was increased at arate of 20° C./minute to a final oven temperature of 200° C. Thecompounds of interest were quantified by comparing peak integrationvalues to a tetradecane internal standard. The concentration of thefollowing compounds was determined in parts-per-million (ppm):acrylamide (ACM), isooctyl acrylate (IOA),2,2′-azobis(2,4-dimethylvaleronitrile) (ABVN), isooctyl alcohol (IOOH),and isooctyl acetate (IOAc). The minimum detection limit (MDL) for ACMand ABVN was 8 ppm. The BDL for IOA, IOOH and IOAc was 26 ppm. Thedesignation BDL refers to Below Detection Limit. Samples for analysiswere prepared by precipitating a sample of the copolymer solution withmethanol. A sample from the methanol phase was then injected into thegas chromatograph. The analysis for residual monomer and initiator, aswell as IOOH and IOAc, in samples of Copolymer A, Copolymer B (sampleafter 3 wash procedures), and samples after one and two wash treatmentsis presented in Table 1.

TABLE 1 Concentration of Residual Monomers and Monomer DerivedImpurities ACM IOA IOOH IOAc Sample (ppm) (ppm) (ppm) (ppm) Copolymer A222 779 2602 2016 Sample after 1^(st) wash 66 258 2313 590 treatmentSample after 2nd wash BDL 37 1496 143 treatment Copolymer B (Sample BDLBDL 205 BDL after 3rd wash treatment)

It is noted that because vinyl acetate is relatively volatile,essentially no vinyl acetate was expected in the copolymer adhesive ofthe devices described herein subsequent to device preparation. For thisreason, analysis for vinyl acetate was not conducted in this Example.However, analysis for vinyl acetate in methanol extractions prepared asin Example 3 from devices made as in Example 2 showed that no detectablevinyl acetate was present.

Additional lots of Copolymer A and Copolymer B were prepared accordingto the procedure above and used to determine the concentration of thefree radical initiator 2,2′-azobis(2,4-dimethylvaleronitrile) (ABVN) ineach copolymer. The gas chromatography test method described above wasused. The minimum detection limit (MDL) for ABVN was 8 ppm.

TABLE 2 Concentration of Initiator ABVN Sample (ppm) Copolymer A 332Sample after 1^(st) wash NT treatment Sample after 2nd wash NT treatmentCopolymer B (Sample BDL after 3rd wash treatment) NT = Not Tested

Example 2

A transdermal drug delivery (TDD) device using Copolymer A was preparedas follows. (S)—N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenylcarbamate (1.8020 g) was added to a jar, followed by solvated CopolymerA ((32.6859 g) 25 weight % solids in a 25/75 Methanol/Ethyl Acetatesolvent mixture). The solution was mixed on a shaker until a uniformmixture was obtained. The solution was coated using a knife set todeliver a wet thickness of 25 mil (0.025 inches or 0.635 mm) ontoLoparex 5 CL PET 4400x release liner (available from Loparex Company,Cary, N.C.). The coated liner was then oven dried (for 12.5 minutes at125° F. (52° C.)) and laminated onto a ScotchPak 9732 backing (availablefrom 3M Company, St. Paul, Minn.). The resulting adhesive coatingcontained 18 weight % of(S)—N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate. The TDDdevices were configured as circles with surface areas of 1, 5 or 10 cm².

TDD devices prepared with Copolymer A were analyzed for residualmonomers and initiator by gas chromatography using an HP-6890 gaschromatograph equipped with a split/splitless injection port and flameionization detector (Hewlett Packard, Palo Alto, Calif.). The analyticalcolumn used was a Rtx-Volatiles (30 meters, 0.32 mm ID, 1.5 micron)capillary column (Restek, Bellefonte, Pa.). The injection port was setto 270° C. and the flame ionization detector was set to 290° C. The oventemperature was set to 60° C. and the temperature was increased at arate of 10° C./minute to a final oven temperature of 280° C. Thecompounds of interest were quantified by comparing peak integrationvalues to an ethyl laurate internal standard. The concentration of thefollowing compounds was determined in parts-per-million (ppm):acrylamide (ACM), isooctyl acrylate (IOA), and2,2′-azobis(2,4-dimethylvaleronitrile) (ABVN). The minimum detectionlimit (MDL) for ACM was 12 ppm. The MDL for IOA was 11 ppm. The MDL forABVN was 14 ppm. The designation BDL refers to Below Detection Limit.The liner was removed from a TDD device and the backing and coating wereextracted using methanol. A sample from the methanol phase was theninjected into the gas chromatograph. A total of three TDD devices weresampled and the results are presented as the average from the threesamples.

TDD devices prepared with Copolymer A were analyzed for vinyl acetate(VOAc) by gas chromatography using an HP-6890 gas chromatograph equippedwith a split/splitless injection port and flame ionization detector(Hewlett Packard, Palo Alto, Calif.). The analytical column used was aRtx-1701 (30 meters, 0.32 mm ID, 1.0 micron) capillary column (Restek,Bellefonte, Pa.). The injection port was set to 220° C. and the flameionization detector was set to 280° C. The oven temperature was set to40° C. and the temperature was increased at a rate of 35° C./minute to afinal oven temperature of 280° C. The concentration of vinyl acetate wasquantified by comparing peak integration values to an acetonitrileinternal standard. The concentration of vinyl acetate (VOAc) wasdetermined in parts-per-million (ppm). The minimum detection limit (MDL)for VOAc was 42 ppm. The designation BDL refers to Below DetectionLimit. A total of three TDD devices were sampled and the results arepresented as the average from the three samples. The results are shownin Table 3

TABLE 3 Concentrations of Monomers and Initiator in TDD Devices withCopolymer A IOA ACM VOAc ABVN Description (ppm) (ppm) (ppm) (ppm)Example 2 242 92 BDL 312 (Copolymer A )

Example 3

The exact same procedure and analytical test methods as described inExample 2 was used to prepare and analyze TDD devices containingsolvated Copolymer B, except that Copolymer B was used instead ofCopolymer A. The results are shown in Table 4.

TABLE 4 Concentrations of Monomers and Initiator in TDD Devices withCopolymer B IOA ACM VOAc ABVN Description (ppm) (ppm) (ppm) (ppm)Example 3 BDL BDL BDL BDL (Copolymer B )

Example 4

The TDD devices described in Examples 2 and 3 were sealed in pouches(BAREX™/aluminum/paper laminates) and stored under conditions of 60°C./ambient humidity. The TDD devices were tested for percent totalimpurities within 1 week after preparation and at preset storage times(1 month and 2 months after preparation) using the following testmethod.

The liner was removed from a TDD device and the TDD device was placed ina 40 mL vial. The backing and coating were extracted using 20 mL ofmethanol solvent. The sample was shaken overnight. An aliquot from thesample was analyzed for percent total impurities by high performanceliquid chromatography using an Agilent 1100 liquid chromatographequipped with an ultraviolet detector (Agilent Technologies, SantaClara, Calif.). The analytical column used was an XBridge C18, 75×4.6mm, 3.5 mcm particle size HPLC column (Waters Corporation, Milford,Mass.). Analytes were separated using reversed-phased gradient elutionchromatography. A linear gradient from 10-90% acetonitrile over 30minutes was used at a flow rate of 1 mL/min. The compounds of interestwere quantified by comparing peak integration values to an(S)—N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamatereference standard and the sum of these compounds are presented in Table5 as percent total impurities. At each time point a total of three TDDdevices were sampled and the results are presented as the average fromthe three samples.

TABLE 5 TDD Devices from Examples 2 and 3 Stored at 60° C. and AmbientHumidity Percent Total Impurities Description Initial 1 month 2 monthsTDD devices prepared 0.26 1.45 2.12 with Copolymer A TDD devicesprepared 0.14 0.75 0.95 with Copolymer B

Example 5

A TDD device spiked with ABVN initiator was prepared as follows.(S)—N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate (1.7963g) was added to a jar, followed by solvated Copolymer B ((32.5988 g) 25weight % solids in a 25/75 Methanol/Ethyl Acetate solvent mixture).2,2′-Azobis(2,4-dimethylvaleronitrile) (ABVN) (0.0015 g) was added last,and the solution was mixed on a shaker until a uniform mixture wasobtained. The resulting solution was coated using a knife set to delivera wet thickness of 25 mil (0.025 inches or 0.635 mm) onto Loparex 5 CLPET 4400x release liner (available from Loparex Company). The coatedliner was then oven dried (for 12.5 minutes at 125° F.) and laminatedonto a ScotchPak 9732 backing (available from 3M Company, St. Paul,Minn.). The resulting coating contained 18 weight % of(S)—N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate. The TDDdevices were configured as circles with a surface area of 1, 5 or 10cm².

Analysis for ABVN in the adhesive coating was conducted as in Example 2.The result are shown in Table 6.

TABLE 6 Concentration of ABVN Initiator in TDD Devices from Example 5Description ABVN (ppm) Example 5 230

Example 6

The TDD devices described in Example 5 were sealed in pouches(BAREX™/aluminum/paper laminates) and stored under conditions of 60°C./ambient humidity. The TDD devices were tested for percent totalimpurities within 1 week after preparation and after preset storagetimes (1 month and 2 months after preparation) as described in Example4. The results are shown in Table 7.

TABLE 7 TDD Devices from Example 5 stored at 60° C. and Ambient HumidityTotal Percent Impurities Description Initial 1 month 2 months TDD deviceprepared with 0.27 1.20 1.67 Copolymer B and spiked with ABVN initiator(Example 5)

The complete disclosures of the patents, patent documents, andpublications cited herein are incorporated by reference in theirentirety as if each were individually incorporated. Variousmodifications and alterations to this invention will become apparent tothose skilled in the art without departing from the scope and spirit ofthis invention. It should be understood that this invention is notintended to be unduly limited by the illustrative embodiments andexamples set forth herein and that such examples and embodiments arepresented by way of example only with the scope of the inventionintended to be limited only by the claims set forth herein as follows.

1. A transdermal adhesive composition comprising: an adhesive comprisinga washed polymerization reaction product of at least two ethylenicallyunsaturated monomers; and at least one pharmaceutically active compoundwhich is susceptible to oxidative degradation; wherein the at least twoethylenically unsaturated monomers, if present in the adhesive asunreacted monomers, are present at a level of less than 200 ppm of totalunreacted monomer, based upon the total weight of the adhesive; andwherein any free radical initiator, if present in the adhesive, ispresent at a level of less than 20 ppm, based upon the total weight ofthe adhesive.
 2. A transdermal adhesive composition comprising: anadhesive comprising a washed polymerization reaction product of at leasttwo ethylenically unsaturated monomers; and(S)—N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate or apharmaceutically acceptable salt thereof; wherein the at least twoethylenically unsaturated monomers, if present in the adhesive asunreacted monomers, are present at a level of less than 200 ppm of totalunreacted monomer, based upon the total weight of the adhesive.
 3. Thecomposition of claim 2, wherein any free radical initiator, if presentin the adhesive, is present at a level of less than 20 ppm, based uponthe total weight of the adhesive. 4-12. (canceled)
 13. A transdermaldrug delivery device comprising: a transdermal adhesive compositioncomprising: an adhesive comprising a washed polymerization reactionproduct of at least two ethylenically unsaturated monomers; and at leastone pharmaceutically active compound which is susceptible to oxidativedegradation; wherein the at least two ethylenically unsaturatedmonomers, if present in the adhesive as unreacted monomers, are presentat a level of less than 200 ppm of total unreacted monomer, based uponthe total weight of the adhesive; and a backing sheet coated with thetransdermal adhesive composition, wherein the transdermal adhesivecomposition coating covers at least a portion of a major surface of thebacking sheet.
 14. (canceled)
 15. The device of claim 13, wherein anyfree radical initiator, if present in the adhesive, is present at alevel of less than 20 ppm, based upon the total weight of the adhesive.16. (canceled)
 17. The device of claim 13, wherein the adhesivecomprises the copolymerization product of at least one first monomerselected from the group consisting C₄ to C₁₂ alkyl acrylate monomers, C₄to C₁₂ alkyl methacrylate monomers, and combinations thereof; and atleast one second monomer selected from the group consisting ofacrylamide, N,N-diethylacrylamide, methacrylamide, vinyl acetate, vinylalcohol, N-vinyl-2-pyrrolidone, 2-hydroxyethyl acrylate, 2-hydroxyethylmethacrylate, hydroxpropyl acrylate, glyceryl acrylate, 2-ethoxyethylacrylate, 2-ethoxyethoxyethyl acrylate, tetrahydrofurfuryl acrylate,acrylic acid, methacrylic acid, pyrrolidonylethyl acrylate,2-carboxyethyl acrylate, and combinations thereof.
 18. The device ofclaim 17, wherein the at least one first monomer is selected from thegroup consisting of isooctyl acrylate, 2-ethylhexyl acrylate, cyclohexylacrylate, 2-methylbutyl acrylate, butyl acrylate, and combinationsthereof.
 19. The device of claim 13, wherein the adhesive comprises theco-polymerization product of isooctyl acrylate, acrylamide, and vinylacetate.
 20. The device of claim 13, wherein the pharmaceutically activecompound includes at least one group selected from the group consistingof tertiary amino, secondary amino, benzylic hydrogen-containing group,and combinations thereof.
 21. The device of claim 13, wherein thepharmaceutically active compound is selected from the group consistingof: rivastigmine ((S)—N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenylcarbamate), buprenorphine, etidocaine, ropivacaine, clonidine,lidocaine, letrozole, fentanyl, indapamide, apomorphine,propylnorapomorphine, salbutamol, lisuride, dihydroergotamine,pergolide, terguride, proterguride, propranolol, imipramine,guanethidine, cyproheptadine and a pharmaceutically acceptable salt ofany one of the preceding compounds.
 22. The device of claim 21 whereinthe pharmaceutically active compound is(S)—N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate or apharmaceutically acceptable salt thereof.
 23. The device of claim 13,wherein the composition is essentially free of any added antioxidant.24. A method of making a stable transdermal adhesive compositioncomprising: providing a polymerization reaction product of at least twoethylenically unsaturated monomers; and wherein the polymerizationreaction product is dissolved and/or dispersed in a first liquid;separating at least a portion of the polymerization reaction productfrom the first liquid to provide a first washed polymerization reactionproduct; dissolving or dispersing the first washed polymerizationreaction product in a second liquid; separating at least a portion ofthe first washed polymerization reaction product from the second liquidto provide a second washed polymerization reaction product; wherein theat least two ethylenically unsaturated monomers, if present in thesecond washed polymerization reaction product, are present at a level ofless than 200 ppm of total unreacted monomer, based upon the totalweight of the second washed polymerization reaction product; andcombining the second washed polymerization reaction product with atleast one pharmaceutically active compound which is susceptible tooxidative degradation to form a stable transdermal adhesive composition.25. The method of claim 24, further comprising: dissolving or dispersingthe second washed polymerization reaction product in a third liquid;separating at least a portion of the second washed polymerizationreaction product from the third liquid to provide a third washedpolymerization reaction product; and combining the third washedpolymerization reaction product instead of the second washedpolymerization reaction product with the at least one pharmaceuticallyactive compound which is susceptible to oxidative degradation to formthe stable transdermal adhesive composition
 26. The method of claim 24,wherein the separating, in each instance, is carried out by adding awash liquid to the dissolved polymerization reaction product, allowingpolymerization reaction product to precipitate, and separating theprecipitate from the liquid, to provide washed polymerization reactionproduct.
 27. The method of claim 24, further comprising polymerizing theat least two ethylenically unsaturated monomers dissolved in the firstliquid to provide the polymerization reaction product dissolved and/ordispersed in the first liquid.
 28. The method of claim 24, wherein theat least two ethylenically unsaturated monomers, if present in thewashed polymerization reaction product combined with the at least onepharmaceutically active compound, are present at a level of less than100 ppm total unreacted monomer, based upon the total weight of thewashed polymerization product.
 29. The method of claim 24, wherein anyfree radical initiator, if present in the washed polymerization productcombined with the at least one pharmaceutically active compound, ispresent at a level of less than 20 ppm, based upon the total weight ofthe washed polymerization reaction product.
 30. (canceled)
 31. Themethod of claim 24, wherein the adhesive comprises the copolymerizationproduct of at least one first monomer selected from the group consistingC₄ to C₁₂ alkyl acrylate monomers, C₄ to C₁₂ alkyl methacrylatemonomers, and combinations thereof; and at least one second monomerselected from the group consisting of acrylamide, N,N-diethylacrylamide,methacrylamide, vinyl acetate, vinyl alcohol, N-vinyl-2-pyrrolidone,2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, hydroxpropylacrylate, glyceryl acrylate, 2-ethoxyethyl acrylate, 2-ethoxyethoxyethylacrylate, tetrahydrofurfuryl acrylate, acrylic acid, methacrylic acid,pyrrolidonylethyl acrylate, 2-carboxyethyl acrylate, and combinationsthereof.
 32. The method of claim 31, wherein the at least one firstmonomer is selected from the group consisting of isooctyl acrylate,2-ethylhexyl acrylate, cyclohexyl acrylate, 2-methylbutyl acrylate,butyl acrylate, and combinations thereof.
 33. The method of claim 24,wherein the adhesive polymer comprises the co-polymerization product ofisooctyl acrylate, acrylamide, and vinyl acetate.
 34. The method ofclaim 24 wherein the pharmaceutically active compound includes at leastone group selected from the group consisting of tertiary amino,secondary amino, benzylic hydrogen-containing group, and combinationsthereof.
 35. The method of claim 24, wherein the pharmaceutically activecompound is selected from the group consisting of: rivastigmine((S)—N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate),buprenorphine, etidocaine, ropivacaine, clonidine, lidocaine, letrozole,fentanyl, indapamide, apomorphine, propylnorapomorphine, salbutamol,lisuride, dihydroergotamine, pergolide, terguride, proterguride,propranolol, imipramine, guanethidine, cyproheptadine and apharmaceutically acceptable salt of any one of the preceding compounds.36. The method of claim 35, wherein the pharmaceutically active compoundis (S)—N-ethyl-N-methyl-3-[1-(dimethylamino)ethyl]phenyl carbamate or apharmaceutically acceptable salt thereof.
 37. The method of claim 24,wherein an antioxidant is not added to the stable transdermal adhesivecomposition. 38-39. (canceled)